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The Role of the E3 ligase Huwe1 in mental and intellectual disorders

Drs. Manabu Kurokawa (Biological Sciences, ºÚÁÏÍø), Takhar Kasumov (Pharmaceutical Sciences, NEOMED) and Wilson Chung (Biological Sciences, ºÚÁÏÍø)

Ubiquitination is a protein post-translational modification in which the small peptide ubiquitin is covalently conjugated to a substrate protein. Ubiquitination plays multiple key roles in cellular homeostasis by affecting the activity or function of target proteins, altering protein subcellular localization, and promoting protein degradation through the ubiquitin-proteasome pathway. Ubiquitination consists of three steps: activation of ubiquitin by ubiquitin-activating enzymes (E1), transfer of ubiquitin from E1 to ubiquitin-conjugating enzymes (E2), and ligation of ubiquitin to a substrate lysine by E3 ubiquitin ligases. The E3 ligase family consists of more than 600 enzymes and is known to be involved in a number of human diseases. Recently, several studies have reported mutations or copy number amplification of the Huwe1 gene, encoding an E3 ligase, in patients with mental disorders, including schizophrenia and intellectual disabilities. Interestingly, most of the mutations are located in the catalytic domain as a single point mutation, suggesting that they may affect the activity of Huwe1. This project will identify the specific substrate(s) of Huwe1, or an altered proteomic landscape caused by Huwe1 mutations, using brain tissues and embryonic fibroblasts isolated from Huwe1 transgenic mice. Despite the presence of numerous studies on neurodevelopmental disorders, the mechanisms that regulate them remain poorly understood. We expect that the identification of a Huwe1 substrate(s) or an altered proteomic landscape will uncover a novel signaling mechanism causing the neurodevelopmental disorders and may lead to new therapeutic opportunities.